A defining pathological feature of Parkinson's disease (PD) is the abnormal accumulation of alpha-synuclein protein deposits within the brain into what are known as Lewy bodies. The accumulation of alpha-synuclein within the brain leads to the progressive death of dopaminergic neurons and downstream cognitive and behavioral impairments. In addition to PD, aggregation of alpha-synuclein is also associated with a broad group of neurodegenerative diseases known collectively as synucleopathies; examples include dementia with Lewy bodies, multiple system atrophy, Pick's disease, and corticobasal degeneration. Similarly, alpha-synuclein protein deposits and Lewy bodies are often associated with the development of Alzheimer's disease.1 Augmentation of β-glucocerebrosidase (GCase, EC. 3.2.1.45) activity in a mouse model of PD has been implicated in reduced alpha-synuclein accumulation and delayed onset of pathology.2,5 In addition, small-molecule GCase modulators have been shown to reduce alpha-synuclein levels and behavioural deficits in a rodent model of PD.6,7 
Gaucher's disease (GD) is a lysosomal storage disorder caused by homozygous loss of function mutations in GBA1, the gene encoding GCase.8 Normally, GCase present within lysosomes catalyzes hydrolytic cleavage of glucose from the glycolipid glucocerebroside (also known as glucosylceramide) within this compartment of cells. In Gaucher's disease, lysosomal GCase levels are greatly reduced or functionally absent, leading to the pathological accumulation of glucosylceramide within lysosomes. Symptoms of Gaucher's disease may include some or all of the following: enlarged spleen and liver; liver malfunction; skeletal disorders and bone lesions that may be painful; severe neurologic complications; swelling of lymph nodes and (occasionally) adjacent joints; distended abdomen; a brownish tint to the skin; anemia; low blood platelets and yellow fatty deposits on the sclera. In addition, persons affected with Gaucher's disease may be more susceptible to various infections. Current treatment of Gaucher's involves administering recombinant human GCase as an enzyme replacement therapy (ERT), which helps to control the visceral and haematological complications of Gaucher's disease. However, because the recombinant enzyme is not brain-penetrant, ERT does not improve the neurological manifestations of the disease.
International patent applications PCT/US2004/037704, filed 12 Nov. 2004, published under No. WO 2005/046612 on 26 May 2005; PCT/US2007/072016, filed 25 Jun. 2007, published under No. WO 2007/150064 on 27 Dec. 2007; PCT/US2010/030470, filed 9 Apr. 2010, published under No. WO 2010/118282 on 14 Oct. 2010; PCT/US2010/051447, filed 5 Oct. 2010, published under No. WO 2011/049736 on 28 Apr. 2011; PCT/US2010/051458, filed 5 Oct. 2010, published under No. WO 2011/049737 on 28 Apr. 2011; PCT/CA2012/001084, filed 23 Nov. 2012, published under No. WO 2013/075227 on 30 May 2013; PCT/US2013/029612, filed 7 Mar. 2013, published under No. WO 2013/148103 on 3 Oct. 2013, are directed to small-molecule modulators of GCase.